PROJECT 3: Human dendritic cells and the onset of innate andadaptive immunity in allogeneic hematopoietic transplantation This new project will adhere to the thematic emphasis of this P01 on the early events after allogeneic hematopoietic stem cell transplantation (alloHSCT) that promote immune reconstitution and sustain freedom from relapse. T cell responses against minor histocompatibility Ags (miHA) and development of the natural killer (NK) cell repertoire are critically intertwined with these processes occurring early post-transplant. To improve our understanding of the biologic mechanisms underlying these immune responses, we will focus on the afferent, rather than efferent or effector arm of the immune response, and identify the distinct roles played by defined subtypes of human dendritic cells (DCs). These will then be tested in a preclinical mouse model. Our intention is eventually to target immune-based interventions to one or another DC subtype, in order to isolate the complications of graft-vs-host disease (GvHD), from the desired benefits of graft-vs- tumor/leukemia/lymphoma (GvT/GvL) and successful reconstitution of innate and adaptive immunity, at the level of antigen presentation. We will therefore approach these issues by (1) testing whether CD34+-derived Langerhans-type dendritic cells (LCs) stimulate more robust T cell responses against minor histocompatibility Ags (miHA) than do the other two types of conventional or myeloid DCs; (2) determining which human DC type is most effective in shaping the NK cell inhibitory KIR repertoire and the immunologic mechanism(s) by which this occurs; and (3) using mouse transplant models to evaluate the relative potency of bone marrow derived DCs (human monocyte-derived DC counterparts) vs LCs and dermal-interstitial DCs (DDC-IDCs) in GvH and GvT/GvL responses. An improved understanding of the cellular mechanisms underlying these processes, and in particular the contribution of specific DC subtypes, should elucidate control points to manipulate immunologic outcomes after alloHSCT. Lay summary and public health relevance: Specialized white blood cells, called dendritic cells, are critical to the immunity of patients transplanted for leukemia, lymphoma, and other tumors. Understanding the function of dendritic cells in the context of transplantation should help doctors better control the developing immune system. This should favor prevention of disease recurrence and redevelopment of helpful immunity,